The overall goal of this project is to understand the mechanisms by which general anesthetics remove consciousness and allow its return during emergence. Our general hypothesis is that anesthetics remove consciousness by disrupting the functional integration across cortical neuronal networks. The proposed project builds upon our decade-long investigation into the systems neuroscience mechanisms of anesthesia. In our previous work, we focused on the effect of volatile anesthetics on the power and coherence of gamma oscillations, and on their preferential role in cortico-cortical feedback vs. feedforward signaling as a putative neuronal correlate of unconsciousness. Here we extend this work to test the hypothesis for the first time that loss and return of consciousness (righting reflex) in anesthetized rats correlates with reversible, nonlinear transitions in functional connectivity, complexity, and information capacity of the neuronal network. To this end, we will study the concentration-dependent effect of three representative anesthetic agents with substantially different pharmacological profiles: desflurane, propofol, and dexmedetomidine to find a common, agent-invariant neuronal correlate of unconsciousness. As an alternative means of modulating the state of consciousness without changing the anesthetic drug effects, subcortical stimulation of the ascending activating system in the brainstem and basal forebrain will also be performed. Parallel spike trains and local field potentials will be recorded from visual and adjacent association cortices using chronically implanted multielectrode arrays in unrestrained rats, and excitatory and inhibitory connectivity, complexity and information capacity in neuronal networks during both spontaneous ongoing activity and during visual stimulation will be derived. The effect of anesthetics on avalanche dynamics of negative local field potential events will be determined. Local and long-range feedforward and feedback connectivity will be delineated with respect to their cortical layer-specificity. We hypothesize that the diversity of cortical states, ocal and interregional cortical connectivity, and interaction complexity are maximal in the awake, attentive state, reduced by anesthesia when consciousness is lost, reversed by cortical activation, and that the principal target of anesthetic action is feedback connectivity both within and among cortical regions. The proposed work should advance our understanding of the neural mechanism of anesthesia, and more generally, the neurobiological basis of consciousness at an integrative level. The findings should facilitate the development of novel methods for electrophysiological monitoring of the state of consciousness under anesthesia, and the development of new anesthetic agents with specific hypnotic effects. PUBLIC HEALTH RELEVANCE: This research project should help us better understand how general anesthetics work, in particular, how they remove consciousness in the anesthetized patient. The knowledge gained should help develop safer anesthetics and better methods to determine the presence or absence of consciousness during anesthesia. Using anesthetic drugs as investigational tools, the project will also help understand how nerve cells in the brain collaborate to create human and animal consciousness.